Lung cancer is the leading cause of cancer-related death with a 5-year survival rate less than 15%. In this heterogeneous disease, Epidermal growth factor receptor (EGFR) is one of the main oncogenic drivers. EGFR plays a critical role in lung cancer development and progression. It is highly expressed and frequently mutated in lung malignancies and correlates with poor prognosis. Monoclonal antibodies and small molecule tyrosine kinase inhibitors targeting EGFR were highly effective drugs for treatment of lung cancer, colorectal cancer and squamous cells head and neck carcinoma. However, despite the initial enthusiasm, almost all of patients develop resistance in 1-2 years post treatment. In addition to the classical signaling pathways initiated at the cell surface, EGFR has been reported to be translocated into the nucleus and to be involved in the development of an aggressive phenotype and resistance to therapies. Indeed, within the nucleus, EGFR serves as a: i. transcriptional co-activator for a series of genes involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, chemo and radioresistance; ii. protein kinase and protein-protein interactor. Chronic inflammation is a critical component of cancer progression and a cross-talk between inflammatory mediators, such as Prostaglandin E2 (PGE2) and EGFR has been reported. The aim of this PhD thesis was to assess whether PGE2 contributes to EGFR nuclear translocation. Lung cancer cell lines (A549, GLC82), representative of tumor with high dependency on EGFR axis, were chosen as a model for the study. Here we provided a breakthrough in the field of GPCR-RTK transactivation highlighting the mechanism of PGE2-induced EGFR nuclear translocation. We found that prostaglandin EP3 receptor promotes shedding of membrane-bound EGF-like ligands via Src family kinases/ADAM proteases leading to EGFR activation and consequent internalization. Upon PGE2 treatment, EGFR undergoes to Clathrin- and Caveolin-mediated endocytosis and associates with Importin β1, which promotes its nuclear import. In the nucleus, we observed that PGE2 drives EGFR interaction with STAT3 leading to transcription of genes such as COX-2, iNOS, c-Myc and cyclin D1, which are known to fuel pro-inflammatory microenvironment and tumor progression. In conclusion, our findings indicate that PGE2 promotes EGFR nuclear translocation and contributes to sustain its oncogenic drive suggesting pharmacological targeting of PGE2 as a novel strategy for treatment of NSCLC in combination with chemo and targeted therapy.
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|Titolo:||Prostaglandin E2 promotes EGFR trafficking from cell membrane to the nucleus in human non small cell lung cancer cells|
|Appare nelle tipologie:||8.1 Tesi Dottorato|
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